Abnormal regulation of methylthioadenosine and polyamine metabolism in methylthioadenosine phosphorylase-deficient human leukemic cell lines.
Approximately 30 to 40% of human leukemic cell lines are completely deficient in the purine catabolic enzyme 5'-methylthioadenosine phosphorylase. Using two 5'-methylthioadenosine phosphorylase-negative leukemias, we have for the first time been able to measure the synthesis and biological effects of 5'-methylthioadenosine (MTA) in intact mammalian tumor cells. Malignant cells lacking this enzyme, unlike enzyme-positive cells, excreted MTA into the culture medium at a rate of 0.58 to 0.70 nmol/hr/mg protein. The production of the nucleoside was inhibited effectively by nontoxic concentrations of methylglyoxal bis(guanylhydrazone), a putrescine-depending S-adenosylmethionine decarboxylase inhibitor, and also by spermidine and spermine but was enhanced by putrescine. In a reciprocal fashion, MTA at low concentrations progressively increased both the synthesis and concentration of putrescine but suppressed spermine production. The unique alterations in polyamine metabolism induced by elevated MTA levels could offer a selective growth advantage to the 5'-methylthioadenosine phosphorylase-deficient cells and thus may be related to the high frequency of this enzyme deficiency among human leukemic cell lines.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000172:deficiency / Q000378:metabolism; D002460:Cell Line; D003839:Deoxyadenosines; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D010430:Pentosyltransferases / Q000172:deficiency*; D011073:Polyamines / Q000378:metabolism*; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency*; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013872:Thionucleosides / Q000172:deficiency / Q000378:metabolism*
D003839:Deoxyadenosines; D011073:Polyamines; D013872:Thionucleosides; D013096:Spermine; C008500:5'-methylthioadenosine; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000241:Adenosine; D013095:Spermidine; D011700:Putrescine